A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

The quality of patients' self-blood pressure measurements: a cross-sectional study.

BACKGROUND: The accurate and independent measurement of blood pressure (BP) by patients is essential for home BP monitoring (HBPM) and determining the quality of hypertension (HTN) control. This study aimed to evaluate the BP self-measurement techniques of hypertensive patients and their accuracy in accordance with established guidelines. We sought to identify the common errors that patients make and suggest improvements that can be implemented in the primary healthcare setting to increase the reliability of HBPM conducted by hypertensive patients. METHODS: One hundred patients diagnosed with HTN completed a questionnaire inquiring about their health and demographic data and BP monitoring practices. Patients were then observed and filmed while measuring their BP on their own devices in five primary healthcare centres in Kraków, Poland. The correctness of their techniques was assessed in accordance with the European Society of Hypertension guidelines on HBPM. RESULTS: Only 3% of patients measured their BP without error; 60% made three or more errors. The most frequent error, made by 76% of subjects, was incorrect sphygmomanometer cuff placement (above or below heart level, or/and the indicator mark was not aligned with the brachial artery). Regarding patients' previous instruction for the correct use of their devices, 36% of patients referred to their monitor's user manual, 22% did not receive any prior assistance, and only 29% were adequately counselled by physicians on how to measure their BP correctly. CONCLUSIONS: Our findings suggest that primary healthcare physicians and their personnel often do not adequately instruct patients on how to measure their BP correctly. Therefore, healthcare systems must provide patients with more adequate training and reference materials on the best practices of BP monitoring.

A multicenter retrospective study of 223 patients with t(14;16) in multiple myeloma.

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin <10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age > 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival.

The clinical implication of monoclonal gammopathies: monoclonal gammopathy of undetermined significance and of renal significance.

Monoclonal gammopathy of renal significance (MGRS) has introduced a new perspective to several well-known disease entities impacting nephrology, haematology and pathology. Given the constantly changing disease spectrum of these entities, it is clinically imperative to establish diagnostic and treatment pathways supported by evidence-based medicine. MGRS is a disease of the kidney, secondary to plasma cell clonal proliferation or immune dysfunction, requiring therapeutic intervention to eradicate the offending clone. To fully understand the disease(s), it is prerequisite to determine the significance of the findings. The diagnostic work up should be extensive due to the wide heterogeneity of clinical presentation, ultimately necessitating kidney biopsy. Particular patient profiles such as AL amyloidosis, which may be diagnosed through biopsies of other tissues/organs, may be an exception. Treatment decisions should be formulated by multi-disciplinary consensus: nephrologists, haematologists and pathologists. The ultimate goal in managing MGRS is eradication of the offending plasma cell clone which requires targeted chemotherapy and, in eligible cases, haematopoietic stem cell transplantation. We present a review of diagnostic procedures, treatment options and advances in the last few years in the management of MGRS in an effort to acquaint specialists with this new face of several older diseases.

Hematogenous extramedullary relapse in multiple myeloma - a multicenter retrospective study in 127 patients.

The current study assesses the characteristics and outcomes of multiple myeloma (MM) patients, treated with novel agents for hematogenous extramedullary (HEMM) relapse. Consecutive patients diagnosed with HEMM between 2010-2018 were included. Patients' characteristics at diagnosis and at HEMM presentation, response to treatment, survival and factors predicting survival were recorded and analyzed. A group of 127 patients, all diagnosed with HEMM by imaging (87.3%) and/or biopsy (79%), were included. Of those, 44% were initially diagnosed with ISS3, 57% presented with plasmacytomas, and 30% had high-risk cytogenetics. Median time to HEMM was 32 months. In multivariate analysis, ISS3 and bone plasmacytoma predicted shorter time to HEMM (P = .005 and P = .008, respectively). Upfront autograft was associated with longer time to HEMM (P = .002). At HEMM, 32% of patients had no BM plasmacytosis, 20% had non-secretory disease and 43% had light-chain disease. Multiple HEMM sites were reported in 52% of patients, mostly involving soft tissue, skin (29%), and pleura/lung (25%). First treatment for HEMM included proteasome inhibitors (50%), immunomodulatory drugs (IMiDs) (39%), monoclonal antibodies (10%), and chemotherapy (53%). Overall response rate (ORR) was 57%. IMiDs were associated with higher ORR (HR 2.2, 95% CI 1.02-4.7, P = .04). Median survival from HEMM was 6 months (CI 95% 4.8-7.2). Failure to achieve ≥VGPR was the only significant factor for worse OS in multivariate analyses (HR = 9.87, CI 95% 2.35 - 39, P = .001). In conclusion, HEMM occurs within 3 years of initial myeloma diagnosis and is associated with dismal outcome. The IMiDs might provide a higher response rate, and achievement of ≥VGPR predicts longer survival.

Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients.

Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.

Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students.

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

Selective presynaptic enhancement of the prefrontal cortex to nucleus accumbens pathway by cocaine.

The nucleus accumbens (NAc) regulates motivated behavior by, in part, processing excitatory synaptic projections from several brain regions. Among these regions, the prefrontal cortex (PFC) and basolateral amygdala, convey executive control and affective states, respectively. Whereas glutamatergic synaptic transmission within the NAc has been recognized as a primary cellular target for cocaine and other drugs of abuse to induce addiction-related pathophysiological motivational states, the understanding has been thus far limited to drug-induced postsynaptic alterations. It remains elusive whether exposure to cocaine or other drugs of abuse influences presynaptic functions of these excitatory projections, and if so, in which projection pathways. Using optogenetic methods combined with biophysical assays, we demonstrate that the presynaptic release probability (Pr) of the PFC-to-NAc synapses was enhanced after short-term withdrawal (1 d) and long-term (45 d) withdrawal from either noncontingent (i.p. injection) or contingent (self-administration) exposure to cocaine. After long-term withdrawal of contingent drug exposure, the Pr was higher compared with i.p. injected rats. In contrast, within the basolateral amygdala afferents, presynaptic Pr was not significantly altered in any of these experimental conditions. Thus, cocaine-induced procedure- and pathway-specific presynaptic enhancement of excitatory synaptic transmission in the NAc. These results, together with previous findings of cocaine-induced postsynaptic enhancement, suggest an increased PFC-to-NAc shell glutamatergic synaptic transmission after withdrawal from exposure to cocaine. This presynaptic alteration may interact with other cocaine-induced cellular adaptations to shift the functional output of NAc neurons, contributing to the addictive emotional and motivational state.

The reliability of patient blood pressure self-assessments - a cross-sectional study.

OBJECTIVE: Home blood pressure monitoring (HBPM) is an increasingly important tool in managing hypertension (HTN); however, its efficacy depends on its accuracy. This study aimed to explore the differences between blood pressure (BP) measurements conducted by patients and medical professionals and the patient demographic factors correlating with inaccurate self-measured BP levels. METHODS: One hundred hypertensive patients completed a questionnaire inquiring about their health status and HBPM procedures and were filmed while measuring their BP using their own devices. A researcher then measured the patients' BP using a calibrated sphygmomanometer to assess the accuracy of patient-performed readings. This cross-sectional study was conducted in five primary healthcare centers in Kraków, Poland. RESULTS: The mean differences in systolic and diastolic BP readings by patients and researchers were 8.36 mmHg (SD = 10.90 mmHg) and 2.16 mmHg (SD = 9.12 mmHg), respectively. Inaccuracies in patient BP measurements were associated with a less than high school education level, patients' age, and a family history of HTN. CONCLUSION: Patient self-measured BP levels were higher than researcher values, likely due to a higher patient error rate. Healthcare providers must increase training regarding correct HBPM techniques offered to patients; such efforts should be directed at all hypertensive patients, emphasizing the most error-prone demographics.

A silent synapse-based mechanism for cocaine-induced locomotor sensitization.

Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

POEMS Syndrome: Real World Experience in Diagnosis and Systemic Therapy - 108 Patients Multicenter Analysis.

POEMS syndrome, a rare plasma cell disorder, is challenging both in the diagnostic and therapeutic management. We present real word retrospective analysis of 108 cases analyzing clinical features and therapeutic modes. We compare our results with the available literature. This is the first description with such wide use of proteasome inhibitors in first line treatment. POEMS (Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome is a rare and challenging plasma cell disorder, both in the diagnostic and therapeutic management of the disease. Currently, the literature on POEMS is sparse with most evidence being case reports and small case studies. We present a retrospective real world experience of 108 patients with POEMS. We analyzed the clinical features and therapeutic interventions. Regarding clinical features, our findings demonstrated that skin lesions, thrombocythemia and polycythemia were present less frequently than reported previously. Regarding clinical interventions, this is one of the largest analyses of front line treatment in POEMS and the first one to include frequent utilization of proteasome inhibitors (37%). Bortezomib monotherapy was the most effective therapy achieving complete remission/very good partial remissions (CR/VGPR) in 69% of patients. Thirty percent of patients proceeded to planned autologous stem cell transplant (ASCT) as part of the front-line treatment resulting in statistically superior progression-free (PFS) and overall survival (OS) compared to non-ASCT treated patients (P= .003). In multivariate analysis, anemia, thrombocytopenia, and as age over 60 were associated with a negative impact on patient outcomes.

A polygenic risk score for multiple myeloma risk prediction.

There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10-15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10-13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.

Lung Ultrasound Examination in Patients with SARS-CoV-2 Infection: Multicenter Study.

BACKGROUND: The COVID-19 pandemic has, by necessity, contributed to rapid advancements in medicine. Owing to the necessity of following strict anti-epidemic sanitary measures when taking care of infected patients, the accessibility of standard diagnostic methods may be limited. Consequently, the significance and potential of bedside diagnostic modalities increase, including lung ultrasound (LUS). METHOD: Multicenter registry study involving adult patients with confirmed COVID-19, for whom LUS was performed. RESULTS: A total of 228 patients (61% males) qualified for the study. The average age was 60 years (±14), 40% were older than 65 years of age. In 130 from 173 hospitalized patients, HRCT (high-resolution computed tomography) was performed. In 80% of patients, LUS findings indicated interstitial pneumonia. In hospitalized patients multifocally located single B-lines, symmetrical B-lines, and areas of white lung were significantly more frequent as compared to ambulatory patients. LUS findings, both those indicating interstitial syndrome and consolidations, were positively correlated with HRCT images. As compared to HRCT, the sensitivity and specificity of LUS in detecting interstitial pneumonia were 97% and 100%, respectively. CONCLUSIONS: As compared to HRCT, LUS is characterized by a very high sensitivity and specificity in detecting interstitial pneumonia in COVID-19 patients. Potentially, LUS can be a particularly useful diagnostic modality for COVID-19 patients pneumonia.

Genetically determined telomere length and multiple myeloma risk and outcome.

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10-6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

Plasma Cell Leukemia - Facts and Controversies: More Questions than Answers?

Plasma cell leukemia (PCL) is an aggressive hematological malignancy characterized by an uncontrolled clonal proliferation of plasma cells (PCs) in the bone marrow and peripheral blood. PCL has been defined by an absolute number of circulating PCs exceeding 2.0 × 109/L and/or >20% PCs in the total leucocyte count. It is classified as primary PCL, which develops de novo, and secondary PCL, occurring at the late and advanced stages of multiple myeloma (MM). Primary and secondary PCL are clinically and biologically two distinct entities. After the diagnosis, treatment should be immediate and should include a proteasome inhibitor and immunomodulator-based combination regimens as induction, followed by stem cell transplantation (SCT) in transplant-eligible individuals who have cleared the peripheral blood of circulating PCs. Due to the rarity of the condition, there have been very few clinical trials. Furthermore, virtually all of the myeloma trials exclude patients with active PCL. The evaluation of response has been defined by the International Myeloma Working Group and consists of both acute leukemia and MM criteria. With conventional chemotherapy, the prognosis of primary PCL has been ominous, with reported overall survival (OS) ranging from 6.8 to 12.6 months. The use of novel agents and autologous SCT appears to be associated with deeper response and an improved survival, although it still remains low. The PCL prognostic index provides a simple score to risk-stratify PCL. The prognosis of secondary PCL is extremely poor, with OS of only 1 month.

Different MAF translocations confer similar prognosis in newly diagnosed multiple myeloma patients.

The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients - 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) (p = 0.28). Median overall survival (OS) was 54.0 months and 49.0 months, respectively (p = 0.62). Median OS in patients who underwent double autologous stem cell transplantation (ASCT) was 107.0 months versus 60.0 months in patients who received single ASCT (p < 0.001). ISS 3 was associated with shorter OS (HR = 1.89; 95% CI 1.24-3.19; p = 0.005) in Cox analysis. Our study suggests that t(14;20) should be considered as an adverse factor of equal prognostic implication to t(14;16).

Genetic polymorphisms in genes of class switch recombination and multiple myeloma risk and survival: an IMMEnSE study.

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival.

Myocardial injury after endovascular revascularization in critical limb ischemia predicts 1-year mortality: a prospective observational cohort study.

BACKGROUND: Patients with critical limb ischemia (CLI) are at increased risk of cardiovascular complications and mortality. To determine (1) incidence of myocardial injury following endovascular revascularization, and (2) relationship between myocardial injury with 1-year mortality and major adverse cardiovascular events (MACE; i.e., composite of myocardial infarction, stroke, and death). METHODS AND RESULTS: Single-center, prospective cohort study of CLI patients ≥ 45 years of age, who underwent endovascular revascularization with overnight hospitalization. High-sensitive troponins T (hsTnTs) were measured on admission, 3-6 h after endovascular revascularization and the subsequent morning. Myocardial injury after endovascular revascularization was defined as an hsTnT ≥ 14 ng/L with a relative increase ≥ 30% from the baseline value. We also evaluated other myocardial injury hsTnT thresholds (i.e., ≥ 30, ≥ 40, ≥ 60, and ≥ 80 ng/L). 239 consecutive patients (56% male, mean age 71.5 ± 10.1 years) were included; one patient was lost to follow-up. At 1 year, there were 34 deaths (14.2%), and 48 MACE (20.5%). Myocardial injury with the hsTnT threshold of 14 ng/L and relative increase by ≥ 30% from the baseline level occurred in 61 patients (25.5%). Myocardial injury was independently associated with 1-year mortality ([aHR], 2.44; 95% CI 1.18-5.06, for hsTnT ≥ 14 ng/L to aHR, 3.34; 95% CI 1.29-8.65 for hsTnT ≥ 80 ng/L). Myocardial injury was also independently associated with 1-year MACE ([AOR] 2.89; 95% CI 1.41-5.92 for hsTnT ≥ 14 ng/L to AOR, 6.69; 95% CI 2.17-20.68 for hsTnT ≥ 80 ng/L). 85.2% patients who had myocardial injury did not have ischemic clinical symptoms or electrocardiography changes. In sensitive analysis with exclusion of symptomatic patients that developed myocardial injury for the hsTnT ≥ 14 ng/L threshold, both the 1-year mortality (aHR: 2.19; CI 1.02-4.68; p = 0.04), and 1-year MACE (OR 2.25; CI 1.06-4.77; p = 0.036) remained significant. CONCLUSIONS: Myocardial injury is common following endovascular revascularization for CLI and associated with the risk of 1-year mortality and MACE.